Tetrodotoxin - Biochemistry

Biochemistry

Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin, neosaxitoxin and several of the conotoxins also bind the same site.

The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na+ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+ channel). Tetrodotoxin binds to TTX-s Na+ channels with a binding affinity of 5-15 nanomolar, while the TTX-r Na+ channels bind TTX with low micromolar affinity. Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+ channels dominate the rest of the body. The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture.

The toxin blocks the fast Na+ current in human myocytes (the contractile cells of the muscles), thereby inhibiting their contraction. By contrast, the sodium channels in pacemaker cells of the heart are of the slow variety, so action potentials in the cardiac nodes are not inhibited by the compound. Note, the SA and AV nodes do not contain Na+ channels only Ca2+ channels, only the Purkinje fibers contain Na+ channels. The myocytes in the atrium, which surround the main cardiac pacemaker, do express this fast Na+ current and therefore the electrical activity is blocked and the heart fails to beat.

Blocking of fast Na+ channels has potential medical use in treating some cardiac arrhythmias. Tetrodotoxin has proved useful in the treatment of pain (originally used in Japan in the 1930s) from such diverse problems as terminal cancer, migraines, and heroin withdrawal.